This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The Influenza Pathogenesis &Immunology Research Center (IPIRC) is one of six national Influenza Centers of Excellence funded by NIH/NIAID. The objectives of this Center are to determine the molecular, ecologic and/or environmental factors influencing the evolution, emergence, transmission and pathogenicity of influenza viruses, including studies on animal influenza viruses with pandemic potential;and to characterize the immune response to influenza vaccination to improve understanding of immune correlates of protection and cross-protection. Most immune responses follow Burnet's rule, that antigen recruits specific lymphocytes from a large repertoire and induces them to proliferate and differentiate into effector cells. However, the phenomenon of "original antigenic sin" stands out as a paradox to Burnet's rule of B cell engagement. Humans, upon infection with a novel influenza strain, produce antibodies against older viral strains at the expense of responses to novel, protective antigenic determinants. This exacerbates the severity of the current infection. We visited this issue to determine the extent to which original antigenic sin is induced by variant influenza viruses. Using two related strains of influenza A virus, we have shown that original antigenic sin leads to a significant decrease in development of protective immunity and recall responses to the second virus. In addition, we have been able to show that sequential infection of mice with two live influenza virus strains leads to almost exclusive antibody responses to the first viral strain, suggesting that original antigenic sin could be a potential strategy by which variant influenza viruses subvert the immune system.